An ultimate goal of HIV/AIDS research is the development of a vaccine that prevents HIV infection, which will be needed for eliminating HIV/AIDS in the U.S. and globally. Randomized clinical trials that rigorously assess the efficacy of candidate HIV vaccines are a core research approach to meeting this goal. This project develops statistical methods for HIV vaccine efficacy trials and for parallel repeated low-dose challenge trials of SIV vaccines in nonhuman primates. For efficacy trials. Aims 1 and 2 develop novel and interdigitating statistical methods for: (1) sieve analysis, i.e., the assessment of how vaccine efficacy against HIV infection varies with genetic features of transmitting HIVs; and (2) immune correlates of protection analysis, i.e., the assessment of how vaccine efficacy against HIV infection and against genotype-specific HIV infection varies with immune responses to vaccination. The overarching objective of these two aims is development of immune correlates of protection (CoPs), which are needed for guiding the optimal choice of HIV sequences to include in vaccines, for guiding the choice of immunogenicity endpoints for benchmarking refined vaccine regimens in Phase l/ll trials, and for immuno-bridging of efficacy trial results to predict vaccine efficacy in new settings. The methods will focus on (A) efficiently and flexibly accommodating time- variations in vaccine efficacy; (B) maximizing the immunological relevance ofthe HIV genetic features; (C) improving the sampling design for measuring immune responses; and (D) developing the best threshold or score immune CoPs that combine information from the large set of immune responses that are assessed. Many ofthe new methods will improve validity, efficiency, and robustness via the targeted maximum likelihood statistical framework. The methods will be developed with application to 13 vaccine efficacy trials (8 for HIV, 3 for dengue, 1 for herpes zoster, 1 for influenza). Aim 3 parallels Aims 1 and 2 by developing novel statistical methods for assessing within nonhuman primate repeated low-dose challenge trials how vaccine efficacy to prevent SIV infection over time varies with genetic features of exposing SIVs and with immune responses to vaccination. The Aim 3 research plan focuses on issues (A), (B), and (D)and will be developed with application to several trials from three research groups. RELEVANCE (See instructions): A vaccine that prevents HIV infection is needed for eliminating HIV/AIDS in the U.S. and globally. Such avaccine may be developed through a series of vaccine efficacy trials that identify candidate vaccines conferring partial protection against HIV infection, and that identify how the protection varies with the genetics of HIV and with immune responses to vaccination. This project develops novel statistical methods for improving and accelerating this process; these methods also apply to the development of vaccines for other infectious diseases.